Patent EA-003261-B1 (EA)
Title: Reactive crystallization method to improve particle size
Inventor: AM ENDE DAVID JOHN
IPC: C07D417/12
Filed: 2001-05-25
Abstract: 1. A process far synthesis and crystallization of a chemical compound comprising contacting one ar more jet steams of a solution in a first solvent of a first reactive intermediate and one or more jet streams of a solution in a second solvent of a second reactive intermediate, said jet streams impinging to create high turbulence at their point of impact under conditions of temperature and pressure which permit reaction of said first and second reactive intermediates to produce a product; and selecting said first and second solvents so that said product is of limited solubility in a mixture of said first and second solvents. 2. The process of claim 1, wherein one of said first and second reactive intermediates is a basic intermediate and the other intermediate is an acidic intermediate. 3. The process of claim 1, wherein one of said first and second reactive intermediates is a zwitterion and the other intermediate is an acid. 4. The process of claim 1, wherein one of said first and second reactive intermediates is a zwitterion and the other intermediate is a base. 5. The process of claim 1, wherein one of said first and second reactive intermediates is an organic salt form and the other intermediate is a neutralizing acid compound. 6. The process of claim 1, wherein one of said first and second reactive intermediates is an organic call form and the other intermediate is a neutralizing basic compound. 7. The process of claim 1, wherein said chemical compound is a pharmaceutically acceptable salt selected from the group consisting of: hydrochloride, acetate, besylate, citrate, hydrobromide, D or L lactate, mesylate, succinate, sulfate, D or L tartrate, stearate, tosylate, calcium, potassium, sodium and ethylenediamine. 8. The process of claim 1, wherein the desired product is in the form of crystalline aggregates which are of controlled size. 9. The process of claim 2, wherein one reactive intermediate is ziprasidone free base and the other reactive intermediate is aqueous HCl solution. 10. The process of claim 1, wherein said chemical compound is ziprasidone hydrochloride monohydrate. 11. The process of claim 1, wherein said product is voriconazole free base. 12. The process of claim 2, wherein basic intermediate is selected from sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and said acidic intermediate is voriconazole R-(-)-camphorsulfonic acid salt. 13. The process of claim 1, wherein at least one of said jet streams is directed about 10 degree downward to avoid crystallization of said product in said jets. 14. The process of claim 1, wherein said product produced upon crystallization is solvated. 15. The process of claim 2, wherein one reactive intermediate is 5,8,14-triazatetracyclo[10.3.1.O<2,11>.O<4,9>]-hexadeca-2(11),3,5,7,9-pentaene free base and the other reactive intermediate is a L-tartaric acid solution. 16. The process of claim 1, wherein said chemical compound is 5,8,14-triazatetracyclo[10.3.1.O<2,11>.O<4,9>]-hexadeca-2(11),3,5,7,9-pentaene (L)-tartrate. 17. The process of claim 1, wherein the linear velocity of the jet streams is at least 5 m/sec. 18. The process of claim 1, wherein a sonication probe is included with said impinging jet streams.